Drug delivery to diseased organs, such as the lungs, is challenging especially when the delivery of disease-effective therapeutics is limited, obstructed, or when there is a need to insure location-specific distribution of the drug. Pulmonary delivery of therapeutic drugs provides a number of benefits particularly with regard to absorption area and avoidance of first pass metabolism in the liver. However, meeting the sustained-release goal is somewhat problematic. The lungs tend to expel materials that are introduced and it is therefore difficult to keep the drug in the lung long enough for the sustained release to be effective. Additional challenges revolve around elimination of excipient (enabling delivery of a neat drug), elimination of Chlorofluorocarbon (CFC) propellants in Metered Dose Inhalers (MDI), reduction of the stigma associated with inhalers, and ease of use. Although a natural and safe route, pulmonary delivery has its challenges. The key challenge is getting the drug to reach the deep lung. Historically, aerosol formulations have not been able to move the medication into the deep lung efficiently, and until recently, pulmonary drug delivery systems have been developed to dispense drugs to the airways only for local applications. MDIs, breath-activated dry powder inhalers (DPIs), liquid jet, and ultrasonic nebulizers have proved useful in the management of asthma, but such devices are not designed to deliver drugs into the deep lung. They are not practical for the delivery of most macromolecules because of their low system efficiency, low drug mass per puff, poor formulation stability for macromolecules, and poor dosing reproducibility (Kevin Corkery, Inhalable Drugs for Systemic Therapy, Respir. Care. 45(7), 831-835 (2000)). Studies have established that these particles should range from 1 to 3 μm in diameter for optimal deposition efficiency. Most existing aerosol systems can deliver only a small fraction (about 10-20%) of the dispensed drug in the correct particle size for lung deposition. Furthermore, the amount of drug deposited from the device is highly dependent on the patient's inhalation technique. Any truly effective delivery device for proteins and peptides needs to optimize a patient's ability to inhale correctly (O'Riordan T. G., Palmer, L. B., & Smaldone, G. C. Aerosol deposition in mechanically ventilated patients. Optimizing nebulizer delivery, Am. J. Respir. Crit. Care Med. 149, 214 (1994)).
Most aerosol systems today deliver a total amount of <100 μg of drug per puff to the deep lung; this amount is too low to enable timely delivery of many macromolecules for the required milligram-level doses. Any aerosol system developed for large molecules will have to exhibit a characteristic that is called “payload versatility,” that is, the ability to deliver varying amounts of a drug. Payload versatility will be necessary because the new macromolecule drugs vary widely in potency from a few micrograms to tens of milligrams per dose. Traditional inhalation systems have been designed primarily to deliver some of the most potent drugs in use today, the bronchodilators and bronchosteroids to treat asthma. Both types of compounds are bioactive in the lung at 5-20 μg per dose. In contrast, many peptide and protein compounds need to be delivered to the deep lung at much larger doses of 2-20 mg (Inhalation Delivery of Therapeutic Peptides and Proteins, Akwete L. Adjei and Pramod K. Gupta, editors, Lung Physiology Series, Claude Lenfent, M. D., Series Editor, Marcel Dekker Publishers, 1997; Generation and Characterization of Aerosols for Drug Delivery to the Lungs C B Lalor, A J Hickey—Lung Biology In Health And Disease, 1997—Marcel Dekker Ag).
For inhalation therapies to accomplish their medical goals, macromolecule delivery to the lungs must be precise and consistent at every inspiration. Although the natural bioavailability of the deep lung epithelia appears difficult to change, the efficiency of drug deposition can be improved by utilizing permeation enhancers such as surfactants, fatty acids, and saccharides; and chelating agents and enzyme inhibitors such as protease inhibitors. (Edwards D. Al, Ben-Jebria, A., & Langer, R. Recent advances in pulmonary drug delivery using large, porous inhaled particles. J. Appl. Physiol. 85, 379-385 (1998)). Deposition efficiency from traditional devices, however, remains low with less than 10% of the total inhaled dose reaching the deep lung.
Chitosan nanoparticles have been used to deliver drugs nasally as a therapeutic treatment protocol for asthma and COPD. Although effective medically, delivery of drug-containing nanoparticles through the air way is difficult when there are obstructive airway issues. Nanoparticle delivery is poor (10-30%) and distribution in this way is difficult to control resulting in sub-optimal efficiency.